Process for producing sterile water for injection from potable water

ABSTRACT

By treating potable water at a temperature of at least 230° C. (446° C.) and at a pressure at least equal to the pressure of saturated steam at said temperature, can produce pyrogen-free water using treatment times of 0.05 to 5 seconds or less. The addition of an oxidant, in the form of a gas, a liquid, or a solid, further decreases the required treatment time to less than 0.05 second. The reduction in equipment size achieved with this rapid treatment time allows the utilization of treatment units small enough to be easily transported to remote locations or installed in the restricted space environment existing in ships and submarines.

[0001] This application is a non-provisional application claimingpriority from provisional application Serial No. 60/180,278, filed Feb.4, 2000.

[0002] The U.S. Government has a paid-up license in this invention andthe right in limited circumstances to require the patent owner tolicense others on reasonable terms as provided for by the terms ofcontract N00014-99-M-0254 awarded by the Office of Navel Research,United States Navy.

FIELD OF THE INVENTION

[0003] The present invention relates. to a process and apparatus forproducing sterile water for injection from potable water.

BACKGROUND OF THE INVENTION

[0004] Sterile and pyrogen-free water for injection (WFI) is anessential material for field medical operations requiring parenteralprocedures. Producing, transporting, and storing sufficiently largeamounts of WFI is a key logistical problem. This challenge necessitatesthe development of a compact, reliable, and automatic system that cancontinuously. produce sterile and pyrogen-free WFI from potable watersources. Furthermore, sterile and pyrogen-free WFI can be used toproduce intravenous (IV) fluids and reconstitute freeze-dried bloodproducts. Such devices are particularly useful for ocean vessels toreduce shipboard WFI storage burdens.

[0005] The elimination of all living microorganisms (sterilization) andfever-causing agents i.e. pyrogens (depyrogenation) from water can beaccomplished by physical methods (heat), chemical agents (ethyleneoxide, formaldehyde, alcohol, ozone), radiation, or mechanical methods(filtration). Steam and dry heat are widely used means of sterilization,which can be achieved at temperatures of 121° C. (15 min.) and 180° C.(20 min.), respectively.

[0006] Pyrogens, or bacterial endotoxins, are either metabolic productsof living microorganisms or the constituents of dead microorganisms.Chemically, pyrogens are lipopolysaccharides (LPS) with molecularweights ranging from 15,000 to several million. Both dry pyrogenextracts and pyrogenic aqueous solutions lose little or their activityover years. Therefore, depyrogenation requires satisfactorily hightemperatures and long holding times. Some of the reported data indicatethat 180° C. for 3 to 4 hours, 250° C. for 30 to 45 minutes, or 650° C.for 1 minute under any heat will destroy pyrogens.

[0007] In addition to sterilization and depyrogenation, injectable watermust also be virtually free from particulate matter, oxidizablesubstances, dissolved gases, and metals. Currently, the only acceptableways of manufacturing WFI are distillation and reverse osmosis (RO).However, both methods have limitations when intended for fielddeployment.

[0008] Although distillation is the oldest and most effective method toremove LPS, the distillation still operated under low pressures is bulkyand heat recovery is limited. Distillation and reverse osmosisphysically separate pyrogen from water but neither destroys thepyrogens. The pyrogens concentrated in the distillation still residuesor reverse osmosis retentate must be purged continuously orintermittently from the system. To ensure consistent production ofpyrogen-free water, the equipment must be periodically sterilized todestroy the residual pyrogens that would accumulate on the walls of theequipment.

[0009] As for RO, typically 99.5% to 99.9% of endotoxin load can beremoved in a single pass, and RO filters are not absolute. To produceWFI, both of these methods require additional treatment steps, typicallyinvolving active carbon filters, deionizers, and ultrafiltrationfilters. There is currently a lack of a final heat sterilization method,which is currently required for FDA approval.

SUMMARY OF THE INVENTION

[0010] The present invention includes a fully continuous process toconvert treated potable water to sterile and pyrogen-free water forinjection (WFI) by integrating:

[0011] Hydrothermal processing (HTP) for sterilization anddepyrogenation

[0012] Multi-stage flash evaporation for salt removal and heat recovery

[0013] In-situ filtration for particulate removal

[0014] The key feature of this approach is to expose both feed water andprocess equipment to high temperatures. During the HTP stage of theprocess, the system is maintained at sufficient pressures to preventwater from evaporating. This high-temperature water environment resultsin extremely short treatment times required for sterilization anddepyrogenation, hence enabling the development of a compact andefficient system. To remove electrolytes, the pressure of the system isreduced stepwise to achieve unit operations similar to that of amulti-stage flash evaporation process. By incorporating the microchanneltechnology into the evaporator design, effective heat recovery can beachieved. The entire system including filters is under high heatsterilization conditions so that the possible buildup of bacteria and/orpyrogens during normal operations can be eliminated.

[0015] Since the destruction of pyrogens by HTP is the most criticalstep among the three basic processing steps, initial efforts were madeto prove the proposed HTP concept. To this end, a laboratory-scale HTPsystem was designed, constructed, and operated with a design capacity oftreating 35 gram/min water at temperatures up to 600° C. (1,112° F.) andpressures up to 31 Mpa (4,500 psig). Variations of the reactor residencetime were achieved by adjusting either the feed flow rate (i.e., pumpstroke length and/or frequency) or reactor volume, or both. The feedflow rate typically ranged from 2 ml/min to 30 ml/min. Three reactorassemblies were used to cover a wide range of reactor volumes.Dimensions of these reactor assemblies, reflecting two orders ofmagnitude reactor volume variation from 29.3 ml (1/4-in reactorassembly) to 0.4 ml (1/16-in reactor assembly).

[0016] Using this HTP system, the destruction of an endotoxin (E. coli0113:H10) reached six-orders of magnitude within less than one second ofexposure time. Results derived from these proof-of-concept experimentsare given in Tables 1 to 2.

[0017] Furthermore, a simplified process of the present inventionincludes stacked microchannel chambers consisting of at least two repeatmodules. Each of the microchannel modules consists of independentlyintegrated heat exchanger and evaporator components. These modules areconnected in series.

[0018] As the water leaves the HTP reactor and passes through thepressure letdown device, the pressure of the water. is reduced. As aresult, a portion of the water flashes off in the evaporator section.The vapor portion goes through heat exchange with the incoming feedstream and after pressure reduction is collected as WFI product. Theliquid portion of the water from the evaporator section goes through thepressure letdown device and enters the next microchannel module. Theliquid fraction of the last module, which contains the accumulatedelectrolytes, is discarded as waste stream (reject).

[0019] Sterile, pyrogen-free water is an essential material for medicaloperations requiring parenteral procedures, for producing intravenous(Iv) fluids and reconstituted freeze-dried blood products for injection.The process of the invention allows the continuous production ofpyrogen-free water for injection (WFI) from potable water under fieldconditions. The very short treatment time required to produce WFI usingthe process of the invention allows the use of compact, reliable,automated equipment easily deployable in remote locations wheresimplicity of operation, reliability, and small space requirement arecritical. This process will be particularly useful aboard ships, incombat support medical units, during humanitarian relief operationsfollowing natural disasters and in rural hospitals.

[0020] The process of the invention, by treating potable water at atemperature of at least 230° C. (446° C.) and at a pressure sufficientto keep water in liquid state, i.e. at least the pressure of saturatedsteam at said temperature, can produce pyrogen-free water usingtreatment times of 0.05 to 5 seconds or less. The addition of anoxidant, in the form of a gas, a liquid, or a solid and preferablyhydrogen proxide, further decreases the required treatment time to lessthan 0.05 second. The reduction in equipment size achieved with thisrapid treatment time allows the utilization of treatment units smallenough to be easily transported to remote locations or installed in therestricted space environment existing in ships and submarines.

[0021] Furthermore, the total destruction of pyrogens achieved,eliminates the need for periodic heat sterilization of the equipment.This ensures the production of reliable, consistent WFI quality andsimplifies operations. The application of microchannel technology formultiple effect flash evaporation coupled with heat exchange insures ahigh level of heat economy while producing water essentially free ofdissolved solids from the condensation of the flashed steam. Thedissolved solids are concentrated in the residual water that isdiscarded. The need for a de-ionizer unit as required in conventionalWFI production facilities is therefore eliminated. Because of the hightemperature used in the reactor, it is expected that solids (e.g.;salts, hydroxides, oxides) may deposit on the wall of the reactor and inthe multiple effect flash evaporator. This condition will increase inseverity when temperatures and pressures in excess of the criticaltemperature (374.15° C.) and pressure (22.13 MPa) of water are selectedbecause the solubility of salts decreases significantly in supercriticalwater.

[0022] The process of the invention will remedy this problem byproviding an automatically controlled purged cycle whereby thetemperature in the reactor is decreased periodically to a temperatureselected in the range of 100 to 200° C. to dissolve the deposited solidswhile maintaining sterility of the equipment. The water produced duringthe purge cycle will be discarded and the cycle terminated automaticallywhen the conductivity of the water exiting the process is equal to theconductivity of the feed water. The process of the present inventiontherefore combines pyrogen removal, sterilization, and demineralizationin one simple integrated system where prior art processes required threeseparate processing units.

[0023] These and other objects of the invention, as well as many of theintended advantages thereof, will become more readily apparent whenreference is made to the following description taken in conjunction withthe accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

[0024]FIG. 1 is a schematic illustration of a system for producingsterile and pyrogen-free water for injection.

[0025]FIG. 2 is a process flow diagram of a laboratory scalehydrothermal processing system.

[0026]FIG. 3 is a process flow diagram of a hydrothermal processingsystem according to the present invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0027] In describing a preferred embodiment of the invention illustratedin the drawings, specific terminology will be resorted to for the sakeof clarity. However, the invention is not intended to be limited to thespecific terms so selected, and it is to be understood that eachspecific term includes all technical equivalents which operate in asimilar manner to accomplish a similar purpose.

[0028] With reference to the drawings, in general in FIG. 1 inparticular, the system for producing sterile and pyrogen-free water forinjection embodying the teachings of the subject invention is generallydesignated at 10. With reference to FIG. 1, the system includes an inlet12 for potable water said potable water meeting minimum qualityrequirement specified by the US EPA for drinking water. The water passesinto a heated enclosure, generally designated as 14, as represented byarrow 16. The water passes through a series of microchannel chambers 18as indicated by dotted arrow line 20.

[0029] After passing through microchannel chambers 18, the water asindicated by arrow 32 passes to a hydrothermal processing reactor 34.This water, as indicated by arrow 36 returns to the microchannelchambers 18 for further processing. Some of the water as represented byarrow 24, then passes into filters 24. Water exiting from the filters 22passes, as indicated by arrow 26, into a temperature conditioner asgenerally designated by reference numeral 28. Sterile, pyrogen-freewater for injection is produced as indicated by arrow 30. Waste water asindicated by arrow 38 leaves the microchannel chambers and passesthrough an outlet port as indicated by arrow 40 for proper disposal.

[0030] A power supply 42 powers the operation contained in the heatedenclosure, including heating the enclosure to a temperature of at least230° C. while maintaining a pressure at least equal to the pressure ofsaturated steam at said temperature. The time for producing pyrogen-freewater can be as little as 0.05 to 5 seconds or less.

[0031] In FIG. 2, a laboratory scale hydrothermal processing system isshown. A 100 ml glass bottle 50 as available from Associates of Capecod, as a LAL Reagent Water Bottle, is positioned on an electronic scale52 as available from Denver Instruments, model XS-410, 410 g maximum,0.01 g readability. Water flows through ⅛ inch outside diameterpolyethylene tubing 54 to an air driven pump 56 such as is availablefrom Williams Instruments, model P250 V225-CRTC.

[0032] Another section of ⅛ inch outside diameter X 0.035 inch wallthickness, stainless steel 316 tubing 58 conveys water to a fluidizedsand bed 60 after passing a pressure indicator 62 such as is availablefrom 3-D instruments, 6000 PSI full scale, 20 PSI divisions. In thefluidized sand bed is a coiled preheater and a coiled reactor made ofstainless steel 316 tubing. Thermocouples 64, such as are available fromOmega Engineering, model number CAIN-116U-24, {fraction (1/16)} inchouter diameter, inconel 600, type K, are used.

[0033] Connecting the fluidized sand bed with an ice water bath 66 isanother section 68 of ⅛ inch outer diameter stainless steel 316 tubing.In the ice/water bath is a coiled cooler 70 of ⅛ inch outerdiameter×0.035 inch wall thickness stainless steel 316 tubing.

[0034] From the ice/water bath, is connected a capillary pressurerestrictor 72 of {fraction (1/16)} inch stainless steel 316 tubing,leading to a 10 milliliter sterilized sample vial 74 as is availablefrom American Pharmaceutical Partners, Lot 392462 or Procession GlideNeedle B-D 22G1 1/2 (Becton Dickinson). Also extending from theice/water bath is a back pressure regulator 76 as available fromWhitney, Model SS 4R3A. The regulator leads, by a section 78 of ¼ inchoutside diameter×0.049 inch wall thickness stainless steel 316 tubing,to a 1,000 milliliter glass bottle 80 used as an effluent container. Thedata obtained from the use of this system is found in Tables 1 and 2.

[0035] In FIG. 3, a process flow diagram of a hydrothermal processingsystem 82 is shown. Potable water introduced at arrow 84 is passed intolow temperature filters 86. Waste or rejected water is passed in thedirection of arrow 88.

[0036] The treated potable water moves in the direction of arrow 90 to apump 92. The pump water is then passed in a direction of arrow 94 intostacked microchannel chambers 96 which each include a heat exchangersection 98, an evaporator section 100 and pressure letdown devices 102.In the stacked microchannel chambers, multi-effect flash evaporation iscoupled with heat exchange.

[0037] For pyrogen destruction, sterilization and particulate removal,the water is passed through high temperature filters 104 and electricheaters 106. Ultimately, rejected water is passed in the direction ofarrow 108 whereas sterile, pyrogen free water for injection is passed inthe direction of arrow 110.

[0038] The foregoing description should be considered as illustrativeonly of the principles of the invention. Since numerous modificationsand changes will readily occur to those skilled in the art, it is notdesired to limit the invention to the exact construction and operationshown and described, and, accordingly, all suitable modifications andequivalents may be resorted to, falling within the scope of theinvention. TABLE 1 Run Feed Sample Feed Rxr Rxr Specific Q PyrogenConc.** Time Wt. Duration Rate Temp Pressure Volume at TP RT* (pg/ml)PDE Description (min) (g) (min) (g/min) (C.) (psi) (ml/g) (ml/min) (min)Feed Effluent (%) reactor effluent of Sample #5 3.67 100  2 27.27 388.83500  5.6 152.7 0.02 2500000 <6.0 99.9998 reactor effluent of Sample #64.5 95 2 21.11 303 1700  1.4037 29.6 0.10 2500000 <6.0 99.9998 reactoreffluent of Sample #4 7 81 3 11.57 302 1700  1.4037 16.2 0.18 2500000<6.0 99.99998 reactor effluent of RO water** 23 2 12.33 200 300 1.156414.3 0.21 N/A <6.0 reactor effluent of Sample #3 5 67 2 13.40 200 3001.1564 15.5 0.19 2500000  <6000 99.8 reactor effluent of Sample #2 3.596 2 27.43 196.7 300 1.1564 31.7 0.09 2500000  >6000 <99.8 reactoreffluent of Sample #1 3 95 2 31.67 151.3 300 1.1 34.8 0.09 2500000 >6000 <99.8

[0039] TABLE 2 Sam- ple Run Feed Dura- Feed Rxr Rxr Specific Q PyrogenConc.** Time Wt. tion Rate Temp Pressure Volume at TP RT* (pg/ml) PDEDescription (min) (g) (min) (g/min) (C.) (psi) (ml/g) (ml/min) (min)Feed Effluent (%) reactor effluent of Sample #1 6 80.4 2 13.4 397.4 35005.6 75.0 0.0053 2500000 <6.0 99.9998 (100 ml solution + 1 ml 3% H2O2)reactor effluent of Sample #2 4 62 1.5 15.50 395 3500 5.6 86.8 0.00462500000 <6.0 99.9998 reactor effluent of Sample #3 3 96.6 1 32.20 299.81700 1.4037 45.2 0.0088 2500000 <6.0 99.9998 (100 ml solution + 1 ml 3%H2O2) reactor effluent of Sample #4 2 64.4 1 32.20 300 1700 1.4037 45.20.0088 2500000 <6.0 99.9998 reactor effluent of Sample #2 + 4 2.5 80 132.00 250.7 700 1.1564 37.0 0.011 2500000 <6.0 99.998 reactor effluentof RO water*** 12 356 2 29.67 251 700 1.1564 34.3 0.012 N/A <6.0 reactoreffluent of Sample #5 8 97 4 12.13 204.3 400 1.1 13.3 0.0302500000 >6000 <99.8 (100 ml solution + ml 3% H2O2) reactor effluent ofSample #6 4.86 93 2 19.13 299.8 1700 1.4037 26.8 0.0149 2500000 <6.099.9998 reactor effluent of Sample #7 3.28 95 1 29.00 296.6 1700 1.403740.7 0.0098 2500000 <6.0 99.9998 (100 ml solution + 1 ml 3% H2O2)

We claim:
 1. A system for producing sterile, pyrogen free water forinjection, said system comprising: a hydrothermal processing device forsterilization and depyrogenation of potable water, a multi-stage flashevaporation device for salt removal and heat recovery, and an in-situhigh-temperature filtration device for particulate removal, saidhydrothermal processing device (reactor), said flash evaporation deviceand said filtration device being operable simultaneously for treatingpotable water to sterile, demineralized, pyrogen free water the exposuretime in said hydrothermal processing device (reactor) being less thanfive seconds.
 2. A system as claimed in claim 1, wherein the flashevaporation device includes at least two repeat modules.
 3. A system asclaimed in claim 2, wherein each of the repeat modules includes a heatexchanger section and an evaporator section.
 4. A system as claimed inclaim 1, wherein the potable water is treated at a temperature of atleast 230° C. and at a pressure at least equal to the pressure ofsaturated steam at said temperature.
 5. A system as claimed in claim 4,wherein treatment time for the potable water to sterile, pyrogen freewater is 0.05 to 5 seconds, in the hydrothermal processing reactor.
 6. Asystem as claimed in claim 1, wherein treatment time for the potablewater to sterile, pyrogen free water is less than 0.05 seconds, in thehydrothermal processing reactor.
 7. A system as claimed in claim 1,wherein the hydrothermal processing device includes a purge cycle wherethe temperature is decreased to between 100 to 200° C. to dissolvedeposited solids while maintaining sterility of the equipment.
 8. Asystem as claimed in claim 7, wherein water produced during the purgecycle is discarded from the hydrothermal processing device.
 9. A systemas claimed in claim 6, wherein an oxidant is added to reduce thetreatment time.
 10. A system for producing sterile, pyrogen free waterfor injection, said system comprising: a low temperature filter forreceiving potable water, microchannel chambers for receiving the treatedpotable water from the low temperature filter and for flash evaporationcoupled with heat exchange, high temperature filters connected to themicrochannel chambers, and a hydrothermal processing reactor connectedto the microchannel chambers and the high temperature filters for,pyrogen destruction, sterilization and particulate removal.
 11. A systemas claimed in claim 10, wherein the potable water is treated at atemperature of at least 230° C. and at a pressure at-least equal to thepressure of saturated steam of said temperature.
 12. A system as claimedin claim 11, wherein treatment time in the hydrothermal processingreactor is less than five seconds.
 13. A system as claimed in claim 12,wherein treatment time in the hydrothermal processing reactor is from0.05 to five seconds.
 14. A system as claimed in claim 12, whereintreatment time in the hydrothermal processing reactor is less than 0.05seconds.
 15. A system as claimed in claim 10, wherein the microchannelchambers each include a heat exchanger section and an evaporatorsection.
 16. A system as claimed in claim 15, wherein pressure letdowndevices amongst the microchannel chambers reduce pressure of the potablewater to flash off a portion of the potable water in the evaporatorsection and a vapor portion is caused to pass through the heatexchanger.
 17. A process of producing sterile, demineralized, pyrogenfree water from potable water in a continuous cycle, said processcomprising: passing the potable water through microchannel chambers,passing the potable water through high temperature filters, passing thepotable water through a hydrothermal processing reactor, and maintainingthe microchannel chambers, the high temperature filters and-thehydrothermal processing reactor at a temperature greater than 230° C.and at a pressure greater than the pressure of saturated steam at saidtemperature to produce sterile, demineralized, pyrogen free water frompotable water in a treatment time of less than five seconds, in thehydrothermal processing reactor.
 18. A system as claimed in claim 17,wherein an oxidant is added to reduce treatment time, the hydrothermalprocessing reactor.
 19. A system as claimed in claim 18, wherein theoxidant is in a form of one of a gas, a liquid and a solid.
 20. A systemas claimed in claim 17, wherein a purging cycle is conducted at atemperature in the range of 100 to 200° C. to dissolve deposited solids.